The c-Myc/miR17-92/PTEN Axis Tunes PI3K Activity to Control Expression of Recombination Activating Genes in Early B Cell Development

Appropriate PI3K signals generated by the antigen receptor are essential to promote B cell development. Regulation of recombination activating gene (RAG)-1 and RAG-2 expression is one key process that is mediated by PI3K to ensure developmental progression and selection. When PI3K signals are too high or too low, expression of RAGs does not turn off and B cell development is impaired or blocked. Yet, the mechanism which tunes PI3K activity to control RAG expression during B cell development in the bone marrow is unknown. Recently we showed that a c-Myc/miR17-92/PTEN axis regulates PI3K activity for positive and negative selection of immature B cells. Here, we show that the c-Myc/miR17-92/PTEN axis tunes PI3K activity to control the expression of RAGs in proB cells. Using different genetically engineered mouse models we show that impaired function of the c-Myc/miR17-92/PTEN axis alters the PI3K/Akt/Foxo1 pathway to result in dis-regulated expression of RAG and a block in B cell development. Studies using 38c-13 B lymphoma cells, where RAGs are constitutively expressed, suggest that this regulatory effect is mediated post-translationally through Foxo1.

[1]  Sergei B Koralov,et al.  miRNAs in B Cell Development and Lymphomagenesis. , 2017, Trends in molecular medicine.

[2]  M. Santiago,et al.  Impaired B cell function during viral infections due to PTEN-mediated inhibition of the PI3K pathway , 2017, The Journal of experimental medicine.

[3]  K. Rajewsky,et al.  miRNAs Are Essential for the Regulation of the PI3K/AKT/FOXO Pathway and Receptor Editing during B Cell Maturation. , 2016, Cell reports.

[4]  C. Xiao,et al.  Regulation of B-cell development and tolerance by different members of the miR-17∼92 family microRNAs , 2016, Nature Communications.

[5]  Jiwang Zhang,et al.  Hematopoietic Stem Cell Activity Is Regulated by Pten Phosphorylation Through a Niche‐Dependent Mechanism , 2016, Stem cells.

[6]  S. Shen-Orr,et al.  A c-Myc/miR17-92/Pten Axis Controls PI3K-Mediated Positive and Negative Selection in B Cell Development and Reconstitutes CD19 Deficiency. , 2016, Cell reports.

[7]  K. Ansel,et al.  MicroRNA regulation of lymphocyte tolerance and autoimmunity. , 2015, The Journal of clinical investigation.

[8]  A. Rolink,et al.  The selection of mature B cells is critically dependent on the expression level of the co-receptor CD19. , 2014, Immunology letters.

[9]  Christof Fellmann,et al.  An optimized microRNA backbone for effective single-copy RNAi. , 2013, Cell reports.

[10]  I. Rigoutsos,et al.  The miR-17/92 cluster: a comprehensive update on its genomics, genetics, functions and increasingly important and numerous roles in health and disease , 2013, Cell Death and Differentiation.

[11]  A. Ramiro,et al.  Regulation of B‐cell development and function by microRNAs , 2013, Immunological reviews.

[12]  R. Xavier,et al.  Cutting Edge: Cell-Autonomous Control of IL-7 Response Revealed in a Novel Stage of Precursor B Cells , 2013, The Journal of Immunology.

[13]  R. Pelanda,et al.  Antigen and cytokine receptor signals guide the development of the naïve mature B cell repertoire , 2013, Immunologic research.

[14]  Markus Werner,et al.  FoxO1 induces Ikaros splicing to promote immunoglobulin gene recombination , 2012, The Journal of experimental medicine.

[15]  M. Buitenhuis,et al.  The PI3K/PKB signaling module as key regulator of hematopoiesis: implications for therapeutic strategies in leukemia. , 2012, Blood.

[16]  Ye Ding,et al.  Rapid Generation of MicroRNA Sponges for MicroRNA Inhibition , 2012, PloS one.

[17]  Sheng Ding,et al.  Cooperation between both Wnt/{beta}-catenin and PTEN/PI3K/Akt signaling promotes primitive hematopoietic stem cell self-renewal and expansion. , 2011, Genes & development.

[18]  D. Kitamura,et al.  In-vitro derived germinal centre B cells differentially generate memory B or plasma cells in vivo. , 2011, Nature communications.

[19]  Paul J. Hertzog,et al.  Analysis of microRNA turnover in mammalian cells following Dicer1 ablation , 2011, Nucleic acids research.

[20]  D. Melamed,et al.  The MAPK/ERK and PI(3)K Pathways Additively Coordinate the Transcription of Recombination-Activating Genes in B Lineage Cells , 2010, The Journal of Immunology.

[21]  Markus Werner,et al.  Role of PI3K in the generation and survival of B cells , 2010, Immunological reviews.

[22]  K. Okkenhaug,et al.  The PI3K Isoforms p110α and p110δ Are Essential for Pre–B Cell Receptor Signaling and B Cell Development , 2010, Science Signaling.

[23]  Todd R. Golub,et al.  MicroRNA miR-125a controls hematopoietic stem cell number , 2010, Proceedings of the National Academy of Sciences.

[24]  D. Gilliland,et al.  Constitutively active AKT depletes hematopoietic stem cells and induces leukemia in mice. , 2010, Blood.

[25]  R. DePinho,et al.  PI3 Kinase Signals BCR-Dependent Mature B Cell Survival , 2009, Cell.

[26]  P. Pandolfi,et al.  BCR-mediated apoptosis associated with negative selection of immature B cells is selectively dependent on Pten , 2009, Cell Research.

[27]  Klaus Rajewsky,et al.  MicroRNA Control in the Immune System: Basic Principles , 2009, Cell.

[28]  R. DePinho,et al.  Distinct roles for Foxo1 at multiple stages of B cell differentiation , 2008, Nature Immunology.

[29]  M. Schlissel,et al.  Foxo1 directly regulates the transcription of recombination-activating genes during B cell development , 2008, Nature Immunology.

[30]  R. DePinho,et al.  SLP-65 regulates immunoglobulin light chain gene recombination through the PI(3)K-PKB-Foxo pathway , 2008, Nature Immunology.

[31]  Jing Wang,et al.  Lymphoproliferative disease and autoimmunity in mice with increased miR-17-92 expression in lymphocytes , 2008, Nature Immunology.

[32]  Rudolf Jaenisch,et al.  Targeted Deletion Reveals Essential and Overlapping Functions of the miR-17∼92 Family of miRNA Clusters , 2008, Cell.

[33]  D. Nemazee,et al.  Basal B Cell Receptor-Directed Phosphatidylinositol 3-Kinase Signaling Turns Off RAGs and Promotes B Cell-Positive Selection1 , 2007, The Journal of Immunology.

[34]  M. Reth,et al.  Testing gene function early in the B cell lineage in mb1-cre mice , 2006, Proceedings of the National Academy of Sciences.

[35]  S. Morrison,et al.  Pten dependence distinguishes haematopoietic stem cells from leukaemia-initiating cells , 2006, Nature.

[36]  J. Monroe.  ITAM-mediated tonic signalling through pre-BCR and BCR complexes , 2006, Nature Reviews Immunology.

[37]  D. Melamed,et al.  CD19 regulates positive selection and maturation in B lymphopoiesis: lack of CD19 imposes developmental arrest of immature B cells and consequential stimulation of receptor editing. , 2005, Blood.

[38]  Kong-Peng Lam,et al.  Basal Immunoglobulin Signaling Actively Maintains Developmental Stage in Immature B Cells , 2005, PLoS biology.

[39]  D. Melamed,et al.  Receptor Editing in Positive and Negative Selection of B Lymphopoiesis1 , 2004, The Journal of Immunology.

[40]  J. Cedarbaum.  Survival , 2004 .

[41]  O. Ostrovsky,et al.  Modification of Ligand-independent B Cell Receptor Tonic Signals Activates Receptor Editing in Immature B Lymphocytes* , 2004, Journal of Biological Chemistry.

[42]  R. Rickert,et al.  CD19 Function in Early and Late B Cell Development. II. CD19 Facilitates the Pro-B/Pre-B Transition 1 , 2003, The Journal of Immunology.

[43]  D. Melamed,et al.  Differential c-Myc Responsiveness to B Cell Receptor Ligation in B Cell-Negative Selection 1 , 2003, The Journal of Immunology.

[44]  K. Okkenhaug,et al.  PI3K in lymphocyte development, differentiation and activation , 2003, Nature Reviews Immunology.

[45]  Hong Wu,et al.  Pten inactivation alters peripheral B lymphocyte fate and reconstitutes CD19 function , 2003, Nature Immunology.

[46]  E. Vigorito,et al.  A Crucial Role for the p110δ Subunit of Phosphatidylinositol 3-Kinase in B Cell Development and Activation , 2002, The Journal of experimental medicine.

[47]  H. Igarashi,et al.  Transcription from the RAG1 locus marks the earliest lymphocyte progenitors in bone marrow. , 2002, Immunity.

[48]  Shoham Shivtiel,et al.  Impaired Light Chain Allelic Exclusion and Lack of Positive Selection in Immature B Cells Expressing Incompetent Receptor Deficient of CD191 , 2002, The Journal of Immunology.

[49]  W. Pear,et al.  Ligand-independent Signaling Functions for the B Lymphocyte Antigen Receptor and Their Role in Positive Selection during B Lymphopoiesis , 2001, The Journal of experimental medicine.

[50]  M. Nussenzweig,et al.  Antibody regulation of B cell development , 2000, Nature Immunology.

[51]  D. Nemazee,et al.  B‐cell antigen receptor competence regulates B‐lymphocyte selection and survival , 2000, Immunological reviews.

[52]  T. Kurosaki,et al.  B Cell Antigen Receptor-Induced Activation of Akt Promotes B Cell Survival and Is Dependent on Syk Kinase1 , 2000, The Journal of Immunology.

[53]  F. Rougeon,et al.  Secondary V(D)J Rearrangements and B Cell Receptor-Mediated Down-Regulation of Recombination Activating Gene-2 Expression in a Murine B Cell Line1 , 2000, The Journal of Immunology.

[54]  A. Rolink,et al.  The roles of preB and B cell receptors in the stepwise allelic exclusion of mouse IgH and L chain gene loci. , 1999, Seminars in immunology.

[55]  D. Nemazee,et al.  Developmental Regulation of B Lymphocyte Immune Tolerance Compartmentalizes Clonal Selection from Receptor Selection , 1998, Cell.

[56]  R. Rickert,et al.  Qualitative Regulation of B Cell Antigen Receptor Signaling by CD19: Selective Requirement for PI3-Kinase Activation, Inositol-1,4,5-Trisphosphate Production and Ca2+ Mobilization , 1997, The Journal of experimental medicine.

[57]  W. Cavenee,et al.  Growth suppression of glioma cells by PTEN requires a functional phosphatase catalytic domain. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[58]  M. Sigvardsson,et al.  EBF and E47 collaborate to induce expression of the endogenous immunoglobulin surrogate light chain genes. , 1997, Immunity.

[59]  Tetsuya Nakamura,et al.  The roles of preB cell receptor in early B cell development and its signal transduction , 1997, Immunology and cell biology.

[60]  Klaus Rajewsky,et al.  Impairment of T-cell-dependent B-cell responses and B-l cell development in CD19-deficient mice , 1995, Nature.

[61]  Giles R. Scuderi,et al.  The Basic Principles , 2006 .